Role of NOD2 variants in spondylarthritis

Objective. To investigate the role of the gene NOD2 in susceptibility to, and clinical manifestations of, ankylosing spondylitis (AS). Methods. A case-control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro268 Ser, Arg702 Trp, GlY908 Arg, and Len1007fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls. Associations between NOD2 polymorphisms and several clinical features of AS, including disease severity assessed by questionnaire and age at spondylarthritis onset, were also investigated. Exclusion linkage mapping of chromosome 16 was performed in a separate group of 185 multicase families with AS. Results. An association was identified between Gly908 Arg and UC spondylarthritis (P = 0.016, odds ratio [OR] 4.6, 95% confidence interval [95% CI] 1.316), and a nonsignificant trend with a similar magnitude was observed in association with CD spondylarthritis (P = 0.08, OR 3.9, 95% CI 0.8-18). The Pro268Ser variant was inversely associated with UC spondylarthritis (P = 0.003, OR 0.55, 95% CI 0.37-0.82), but not with CD spondylarthritis. No association was demonstrated between NOD2 variants and primary AS, or between other variants of NOD2 and either UC or CD spondylarthritis. Carriage of the Pro268 Ser polymorphism was associated with greater disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = 0.002). Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset. In primary AS, the presence of a gene with a magnitude of association >2.0 was excluded (exclusion logarithm of odds score less than -2.0), and no association was observed with the microsatellite D16S3136. Conclusion. NOD2 variants do not significantly affect the risk of developing primary AS, but may influence susceptibility to, and clinical manifestations of, colitic spondylarthritis.

Is disease severity in ankylosing spondylitis genetically determined?

Objective. To assess the role of genes and the environment in determining the severity of ankylosing spondylitis. Methods: One hundred seventy-three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent-child pairs, 20 families with both first- and second-degree relatives affected, and 7 families with only second-degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance-components modeling was used to determine the genetic and environmental components Contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models. Results. Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [P = 10-4], BASFI familiality 0,68 [P = 3 × 10-7]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0,36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI. Conclusion. This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.

Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P < 10 4). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P < 10 10) and found evidence for an additional independent association in 4q22/SNCA.A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease. © The Author 2010. Published by Oxford University Press.

The effect of transforming growth factor β1 gene polymorphisms in ankylosing spondylitis

Objectives. To determine whether genetic polymorphisms in or near the transforming growth factor β1 (TGFB1) locus were associated d with susceptibility to or severity of ankylosing spondylitis (AS). Methods. Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index). Results. A weak association was noted between the rare TGFB1 + 1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/ +915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers. Conclusion. This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Medication adherence of individuals with a first episode of psychosis

Objective To determine rates of adherence to antipsychotic medication in first episode patients and the correlates of adherence in this group. Method Subjects were the first 200 admissions to an Early Psychosis Program. Adherence was determined on a three-point scale. Symptoms, medication side-effects, quality of life, substance use and family involvement were examined longitudinally. Results In their first year in the program 39% were non-adherent, 20% inadequately adherent, and 41% adherent. Non-adherent patients demonstrated more positive symptoms, more relapses, more alcohol and cannabis use, reduced insight, and poorer quality of life. They were younger, had an earlier age of onset and less likely to have a family member involved in treatment. Conclusion Results for this group are similar to those reported in the literature. Correlates are often the consequence of non-adherence. Non-compliance has to be anticipated and relationships maintained with patients and families to intervene as soon as possible to minimize the consequence of non-compliance.

A mega-analysis of genome-wide association studies for major depressive disorder

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 x 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 x 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Trait components provide tools to dissect the genetic susceptibility of migraine

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.

G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension

-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein beta3 subunit gene (GNB3) induces formation of a splice variant (Gbeta3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequency=0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group (chi2=22; P=0.00002; odds ratio=2.3; 95% CI=1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolic=105+/-7, 109+/-16, and 128+/-28 mm Hg (mean+/-SD) for CC, CT, and TT, respectively (P=0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (P=0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein beta3 subunit gene in the causation of essential hypertension.

A submission to the Tasmanian Department of Health and Human Services consultation “Healthy Tasmania Five Year Strategic Plan”

This submission will address a number of questions raised in section 5.2, “Potential Future Initiatives to target smoking”, of the Healthy Tasmania Five Year Strategic Plan – Community Consultation Draft. Each question has been answered within this submission. This submission will also address the possibility of legal challenges to these proposed changes, a pivotal consideration when implementing any tobacco control laws. This is due to the aggressive nature of the tobacco industry, as illustrated by their attempts to challenge plain packaging laws in the country and through international treaties. The evidence provided in my submission illustrates that prevention of initiation of smoking during adolescence has various benefits in terms of reduction of negative smoking behaviors in later life. I argue that increasing the minimum legal age of purchasing for tobacco to 21 will benefit both the levels of underage smoking as well as the age of onset of initiation of smoking, due to the greater difficulties that those who are underage would experience in accessing tobacco products. I will also address the question of whether the minimum smoking age should be increased to 25.

Age-related loss of brain volume and T2 relaxation time in youth with type 1 diabetes

OBJECTIVE: Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain. RESEARCH DESIGN AND METHODS: Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient. RESULTS: Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time. CONCLUSIONS: We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified.

African Burkitt Lymphoma: Age-Specific Risk and Correlations with Malaria Biomarkers

African Burkitt lymphoma is an aggressive B-cell, non-Hodgkin lymphoma linked to Plasmodium falciparum malaria. Malaria biomarkers related to onset of African Burkitt lymphoma are unknown. We correlated age-specific patterns of 2,602 cases of African Burkitt lymphoma (60% male, mean ± SD age = 7.1 ± 2.9 years) from Uganda, Ghana, and Tanzania with malaria biomarkers published from these countries. Age-specific patterns of this disease and mean multiplicity of P. falciparum malaria parasites, defined as the average number of distinct genotypes per positive blood sample based on the merozoite surface protein-2 assessed by polymerase chain reaction, were correlated and both peaked between 5 and 9 years. This pattern, which was strong and consistent across regions, contrasted parasite prevalence, which peaked at 2 years and decreased slightly, and geometric mean parasite density, which peaked between 2 and 3 years and decreased sharply. Our findings suggest that concurrent infection with multiple malaria genotypes may be related to onset of African Burkitt lymphoma.

Effects of Mobile Phone Distraction at the Onset of Amber Light: Analysis of Driving Simulator Data

Distraction whilst driving on an approach to a signalized intersection is particularly dangerous, as potential vehicular conflicts and resulting angle collisions tend to be severe. This study examines the decisions of distracted drivers during the onset of amber lights. Driving simulator data were obtained from a sample of 58 drivers under baseline and handheld mobile phone conditions at the University of IOWA - National Advanced Driving Simulator. Explanatory variables include age, gender, cell phone use, distance to stop-line, and speed. An iterative combination of decision tree and logistic regression analyses are employed to identify main effects, non-linearities, and interactions effects. Results show that novice (16-17 years) and younger (18-25 years) drivers’ had heightened amber light running risk while distracted by cell phone, and speed and distance thresholds yielded significant interaction effects. Driver experience captured by age has a multiplicative effect with distraction, making the combined effect of being inexperienced and distracted particularly risky. Solutions are needed to combat the use of mobile phones whilst driving.

Mismatch negativity in recent-onset and chronic schizophrenia : a current source density analysis

Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration-deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia.

Early onset dementia: A narrative review of the literature

Over the past forty years, significant research has been conducted on the epidemiology of late onset dementia. Less is known however, about the prevalence, incidence and burden of illness of early onset dementia (occurring prior to 65 years of age). The purpose of this narrative review is to examine existing literature regarding the experiences and implications of living with early onset dementia for patients, caregivers, and family members. The following questions were addressed: (1) What is the impact of early onset dementia on patients, families and carers? and; (2) What are the needs of patients with early onset dementia and their family and carers? Key findings form this review are presented.

The impact of snares on the continuity of adolescent-onset antisocial behaviour: A test of Moffitt's developmental taxonomy

Moffitt’s dual typology of ‘life-course persistent’ and ‘adolescence limited’ offending has received extensive empirical attention, but the extent to which the antisocial behaviour of adolescence limited offenders is constrained to adolescence is relatively under-examined.Using data from the Australian Mater University Study of Pregnancy and its Outcomes, we explore Moffitt’s concept of snares, or those factors that may lead to an adolescent persisting in antisocial behaviour such as drug addiction, educational failure, and contact with the justice system. The Mater University Study of Pregnancy and its Outcomes is a longitudinal study of mother–child dyads from the pre-natal stage to 21 years of age. Findings show that one-third of individuals identified as having an adolescent onset of antisocial behaviour persisted with this antisocial behaviour as young adults. This continuity can, in part, be explained by snares and the research suggests that reducing exposure to snares may lead to less antisocial behaviour in adulthood.